Diabetes mellitus (DM) has become a serious medical and healthcare issue worldwide. According to the statistics provided by the international Diabetes Federation (IDF), the population of the diabetes patients in the world reached 382 million in 2013, incurring a global medical cost of $548.0 billion, which represents 11% of the total medical expense all over the world. The global medical expense associated to diabetes is expected to reach $627.3 billion in 2035. Insulin is a hormone required for the transformation of sucrose, starch and other food into enemy, and the body's inability to secrete or properly utilize insulin is generally the cause of diabetes. Diabetes is in general classified into type I diabetes (also called insulin-dependent diabetes mellitus, IDDM) and type II diabetes (also called non-insulin-dependent diabetes mellitus NIDDM). Type II diabetes is the most common type and represents around 90% of all diabetes worldwide. The incidence of type II diabetes shows a tendency to keep increasing, because of unhealthy life style in modern society, such as reduced physical exercise and high-calorie diet. The huge market potential has promoted many pharmaceutical companies and research institutes to develop new anti-diabetes targets and medicines.
Currently approved and marketed medicines for type II diabetes mainly include insulin and its analogs, sulfonylureas, biguanides, thiazolinediones (TZDs), α-glucosidase inhibitors, dextrin analogues, incretin analogs, di-peptidyl peptidase IV (DPP-IV) inhibitors, and the like. However, patients taking these hypoglycemic drugs for a long term still fail to have a desired reduction in glycated hemoglobin (HbA1c), and suffer side effects from these drugs, such as hypoglycemia, body weight gain, and cardiovascular risks, which increase the burden on diabetes patients. Hence, there is an urgent demand for a new hypoglycemic drug against type II diabetes that has high efficacy and fewer side effects.
Di-peptidyl peptidase IV (DPP-IV, EC3.4.14.5) is a serine protease which hydrolytically cleaves an N-terminal dipeptide at the last 2nd position from the N-terminus of an L-proline- or L-alanine-containing polypeptide. Although functions of DPP-IV have not been fully elucidated, it is believed to be a major physiological modulating factor for certain modulatory polypeptides, neuropeptides, circulating hormones, and chemotactic factors. Although DDP-IV is a multi-specific enzyme and has a diverse range of substrates, the most common substrates thereof are incretins that include glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins are intestine hormones secreted within a few minutes after intake of nutrients and promoting the processing of the taken nutrients. GLP-1 and GIP show the same effects on β-cells and may improve β-cell functioning, including promoting glucose-dependent insulin secretion, inducing β-cell proliferation and enhancing anti-apoptosis function (Diabetes and Vascular Disease Research 2006 3:159).
Unlike GIP, GLP-1 still promotes insulin secretion in type II diabetes. Therefore, increasing GLP-1 is a promising therapeutic means against type II diabetes (Pharmacol Rev 60:470-512, 2008). GLP-1 may considerably lower the blood sugar level in type II diabetes patients (Lancet, 2002, 359:824-830), but will be rapidly hydrolyzed and inactivated in vivo as a substrate of DPP-IV. Hence, development of DPP-IV inhibitors has great significance for diabetes therapies.
Until now studies on DPP-IV inhibitors have made tremendous advances, and DPP-IV inhibitors including Sitagliptin, Saxagliptin and Alogliptin have been approved and used in clinical settings. DPP-IV inhibitors are highly characteristic in that, since incretins are secreted only after food intake in bodies, DPP-IV inhibitors do not tend to inappropriately increase the insulin level and lead to hypoglycemia, a side effect common to many hypoglycemic drugs. Recent clinical data show that inhibition of DPP-IV may increase insulin secretion, lower blood sugar concentration, and improve functions of β-cells of pancreatic islets (Diabetes, 1998, 47:1253-1258). Typical side effects of DPP-IV inhibitors include respiratory infection, throat pain, diarrhea, common cold-like symptoms, headache, dizziness, and the like. However, in general, DPP-IV inhibitors have good safety and tolerance, and till now patients taking DPP-IV inhibitors have not been found to have severe body weight gain or potential symptoms like body weight loss and edema. In recent years, long-acting DPP-IV inhibitors have drawn particular interest, as they are easy to use and have an ideal hypoglycemic effect, making them more acceptable by type II diabetes patients. A phase-II clinical trial shows that a qw DPP-IV inhibitor Omarigliptin developed by Merck can remarkably lower the blood sugar level. Another qw DPP-IV inhibitor Trelagliptin developed by Takeda Pharmaceutical Co. Ltd. has met the safety and efficacy requirements in the phase-III clinical trial, for which a new drug application has been filed in Japan.
Diabetes (mainly type II diabetes) has its global incidence increasing year by year, and has become the 3rd most threatening non-infectious disease to human health and life following cardiovascular diseases and cancer. Treatment of diabetes has laid down an enormous burden upon families and the society. Therefore, there is a great need for more new and better DPP-IV inhibitors to meet the demand of patients for clinically useful medicines.
Until now several studies on DPP-IV inhibitors have been reported:
(1) US 2007232676 discloses compounds having the following structure, as a DPP-IV inhibitor:
wherein Ar may be a phenyl group substituted with 1 to 5 substituents selected from halogen, hydroxyl, a C1-6 alkyl, and the like; V is selected from groups like
where R3a and R3b are independently selected from hydrogen and a C1-4 alkyl substituted with 1 to 5 fluorine atoms; R2 is selected from groups like hydrogen, hydroxyl, halogen, and carboxyl; R8 is selected from groups like hydrogen and —(CH2)p-phenyl but excludes methylsulfonyl. The detailed descriptions in this patent document are not considered as part of the present invention.
(2) US 20100120863 discloses use of compounds having the following structure as a DPP-IV inhibitor for the treatment or prevention of type II diabetes:
wherein Ar is a phenyl group substituted with hydrogen, alkyl or the like; V is selected from groups like
where R3a and R3b are independently selected from hydrogen and a C1-4 alkyl substituted with 1 to 5 fluorine atoms; R2 is selected from groups like hydrogen, hydroxyl, halogen, and carboxyl; R8 is selected from groups like —SO2—C1-6 cycloalkyl and —SO2—C1-6 alkyl. The detailed descriptions in this patent document are not considered as part of the present invention.
(3) WO 2011103256 discloses that compounds having the following structure have a DPP-IV inhibitor function, for use as a drug for the treatment and/or prevention of diabetes:
wherein Ar is a phenyl optionally substituted with 1 to 5 groups selected from halogen, cyano, hydroxyl, etc.; V is selected from groups like
where R2 is selected from groups like hydrogen, hydroxyl, cyano, halogen, alkyl, alkoxy, and carbonyl; R3a and R3b are selected from hydrogen and a C1-4 alkyl optionally substituted with 1 to 5 fluorine atoms; R8 is selected from groups like hydrogen, alkyl, aryl, cycloalkyl, heteroaryl, and —SO2—C1-6 alkyl. The detailed descriptions in this patent document are not considered as part of the present invention.
(4) WO2007126745 discloses compounds having the following structure as a DPP-IV inhibitor for the treatment of diabetes:
wherein Ar is a substituted or unsubstituted phenyl group, and when substituted, the phenyl is substituted with 1 to 3 substituents selected from halogen, hydroxyl, C1-6 alkyl or the like; V is selected from groups like
where R2 is selected from groups like hydrogen, hydroxyl, halogen, alkenyl, alkynyl, aryl and heteroaryl; R3a and R3b are selected from hydrogen and a C1-4 alkyl substituted with 1 to 5 fluorine atoms; R8 is selected from groups like H, cycloalkyl, phenyl, and alkyl. The detailed descriptions in this patent document are not considered as part of the present invention.
In addition, WO2011103256, WO2008060488, WO2007087231, WO2011037793, WO2011028455, and WO2009025784 also disclose compounds as DPP-IV inhibitors for treatment of diabetes.